The Influence of p53 on Aging is Far From Fully Understood

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The p53 protein sits at the intersection of aging and cancer. Too much p53 activity and cell is activity is shut down, cells are made senescent more aggressively, and this leads to accelerated aging. Too little p53 activity, and precancerous cells might survive to form an ultimately fatal tumor. This is a considerable oversimplification of a very complex set of systems, however. There are plenty of exceptions to the above rule, including examples of conditional upregulation of p53 in mice that both extends life and reduces cancer incidence. The open access paper here discusses some of the complexities and contractions in what is known of the role of p53 – a gene that is well studied, but not yet comprehensively understood.


To accelerate aging, p53 induces apoptosis or cell cycle arrest as a prerequisite to cellular senescence; both can impair the mobilization of stem and progenitor cell populations. To suppress aging, p53 inhibits unregulated proliferation pathways that could lead to cellular senescence and a senescence-associated secretory phenotype (SASP), which creates a pro-inflammatory and degenerative tissue milieu. A review of mouse models supports both possibilities, highlighting the complexity of the p53 influence over organismal aging. These models were originally designed to study cancer but some appear to impact aging and longevity as well. They range from complete p53 null mutations to truncations or point mutations that alter activity. A comparison of these models reveals the complex influence p53 has over organismal aging – which can be independent or a consequence of its tumor suppressor role.

The initial mouse models were simple knockouts that produced no p53 protein. Most p53-/- embryos developed into apparently healthy adults, almost all of which succumb to cancer in about half a year. Heterozygous (p53+/-) mice develop cancer at a later age. Since simple p53-deletion increases cancer, simple overexpression should reduce cancer. Indeed, mice harboring an extra p53 gene contained within a BAC (bacterial artificial chromosome) had a lower incidence of cancer with no obvious effect on aging. Furthermore, increased gene dosage of p53 together with Arf lowered the cancer incidence and improved overall survival. ARF elevates p53 levels by inhibiting MDM2. Similarly, mice with a hypomorphic MDM2 allele, which increased p53 levels, showed a reduced cancer incidence without deleterious side effects. Thus, enhanced p53-mediated cancer suppression was not toxic to adult mice. It is possible that the pro-aging side effects of p53 are manifest only when p53 overwhelms the many regulatory mechanisms that modulate its activity.

The p53-null and p53-elevated mouse models support a simple notion of function; that is, p53 suppresses cancer without toxic side effects. However, other p53-altered mouse models confound this notion. p53 levels influenced aging in mice defective for BRCA1. BRCA1 repairs DNA double strand breaks (DSBs) created during DNA replication as a part of the homologous recombination repair pathway. Deleting one copy of p53 rescued brca1-/- mice from embryonic lethality but these mice displayed an early aging phenotype. Moreover, decreased capacity to repair DSBs caused p53-dependent early cellular senescence in cells and early organismal aging. Another genetic alteration that implicates p53 in aging is REGγ. REGγ-deficient mice display early aging. Elevated p53 might contribute to this phenotype because REGγ is a proteasome activator that regulates p53. Finally, skin-specific MDM2 deficiency resulted in p53-induced senescence in epidermal stem cells and precocious skin aging. These examples are interesting contrasts to the MDM2 hypomorphic allele described above, which reduced cancer without side effects, and suggests that different aspects of p53 regulation, coupled with genetic and environmental variances, can drive distinct biological outcomes.

Further complicating the picture, there are multiple p53 isoforms and family members (p63 and p73) generated from variant promoter usage, alternative splicing, and alternative translation initiation. How these isoforms differ functionally is not fully understood. There is evidence that some of these isoforms could influence aging. For example, expression of the N-terminally truncated p53 isoform in mice lowered cancer risk at the expense of early aging. These mice showed poor tissue regeneration, implicating a defect in stem and progenitor cells. Supporting this possibility, old p53+/- mice exhibited increased levels of hematopoietic stem and progenitor cells, but not if N-terminally truncated p53 was present. The truncated p53 likely forms a tetramer with full-length p53 to improve stability and nuclear localization. Another isoform stabilized p53 in the presence of MDM2. Thus, p53 isoforms have the potential to influence p53 function in a manner that affects aging.

Link: https://doi.org/10.21037/tcr.2016.12.02

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Tackling Amyloid-β Oligomers by Interfering in Specific Interactions Necessary to Protein Aggregation

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The present consensus on the the development of Alzheimer’s disease is that it starts with the accumulation of amyloid-β, though there are many competing theories as to why only some people exhibit this problem to a great enough degree to produce pathology. The biochemistry of oligomers supporting amyloid-β causes sufficient disarray in brain metabolism to set the stage for neuroinflammation, malfunction of immune cells in the brain, and aggregation of altered forms of tau protein into neurofibrillary tangles that cause most of the damage and cell death in the later stages of the condition. The failure to improve outcomes via attempts to remove amyloid-β from the brains of Alzheimer’s patients may be a case of too little, too late, but there is still good reason to remove amyloid-β. Doing so early enough and efficiently enough should prevent the later stages of the condition from developing at all.

The most modern approach to drug development, built atop greatly improved capacities in computation and associated modeling of protein structures and interactions, is to find points of intervention through a greater understanding of how proteins interact with one another, in detail, and how those interactions pertain to disease processes. Researchers can then rationally design molecules that (a) interfere at a vulnerable and highly specific point in a desired interaction and (b) due to this specificity are safe enough for clinical use, as they cause only limited disruption elsewhere in the operation of cellular biochemistry. This is the ideal, in any case. The challenge, as ever, is finding a point of intervention that does in fact turn out to be both specific enough and good enough in practice, in patients.

The research noted here today is an example of this approach to development applied to preventing the aggregation of amyloid-β. In principle, sufficient disruption of the process of forming protein aggregates should allow existing systems of clearance to remove excess or damaged protein molecules before they causes issues. In practice, we shall see how it turns out as this work progresses.

Synthetic peptide can inhibit toxicity, aggregation of protein in Alzheimer’s disease


Alzheimer’s is a disease of aggregation. Neurons in the human brain make a protein called amyloid beta. Such proteins on their own, called monomers of amyloid beta, perform important tasks for neurons. But in the brains of people with Alzheimer’s disease, amyloid beta monomers have abandoned their jobs and joined together. First, they form oligomers – small clumps of up to a dozen proteins – then longer strands and finally large deposits called plaques. For years, scientists believed that the plaques triggered the cognitive impairments characteristic of Alzheimer’s disease. But newer research implicates the smaller aggregates of amyloid beta as the toxic elements of this disease.

Now, researchers have developed synthetic peptides that target and inhibit those small, toxic aggregates. Their synthetic peptides – which are designed to fold into a structure known as an alpha sheet – can block amyloid beta aggregation at the early and most toxic stage when oligomers form. The team showed that the synthetic alpha sheet’s blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer’s. These findings add evidence to the growing consensus that amyloid beta oligomers – not plaques – are the toxic agents behind Alzheimer’s disease. The results also indicate that synthetic alpha sheets could form the basis of therapeutics to clear toxic oligomers in people.

“This is about targeting a specific structure of amyloid beta formed by the toxic oligomers. What we’ve shown here is that we can design and build synthetic alpha sheets with complementary structures to inhibit aggregation and toxicity of amyloid beta, while leaving the biologically active monomers intact.”

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease


Alzheimer’s disease (AD) is characterized by the deposition of β-sheet-rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils.

De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenicCaenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

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Eating Garlic Could Protect Brain Health

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Eating garlic may be good for your brain, particularly as you age. The pungent herb may protect brain health by fighting age-related changes in gut health linked to cognitive function, according to University of Louisville researchers.

The study, which was presented at the American Physiological Society’s 2019 annual meeting, adds more credence to garlic’s status as a superfood, and support for its powerful medicinal properties, which have been valued since ancient times.

A high diversity of gut bacteria tends to be associated with better health, but as you age, gut diversity may decline. At the same time, neurodegenerative diseases including Alzheimer’s and Parkinson’s tend to develop in later life, leading researchers to look into the association between changes in gut microbiota and cognitive decline associated with aging, and how garlic may help.

Garlic Compound Improves Gut Bacteria, Memory

The study involved 24-month-old mice, which is equivalent to between 56 and 69 years in humans. Some of the mice received allyl sulfide, a compound in garlic, which led to improved long- and short-term memory, as well as healthier gut bacteria,1 compared to mice that didn’t receive the supplement.

Mice taking the garlic compound also had higher gene expression of neuronal-derived natriuretic factor (NDNF), a gene required for memory consolidation. Reduced gene expression of NDNF may be linked to cognitive decline.

“Our findings suggest that dietary administration of garlic containing allyl sulfide could help maintain healthy gut microorganisms and improve cognitive health in the elderly,” study author Jyotirmaya Behera, Ph.D., said in a press release.2

The link between gut bacteria and neurological health is not new. People with dementia, for instance, have a different makeup of gut microbiota compared to those without.3 Researchers further explained in the journal Protein & Cell:4

“New researches indicate that gastrointestinal tract microbiota are directly linked to dementia pathogenesis through triggering metabolic diseases and low-grade inflammation progress.

A novel strategy is proposed for the management of these disorders and as an adjuvant for psychiatric treatment of dementia and other related diseases through modulation of the microbiota (e.g. with the use of probiotics).”

That garlic could act as a key modulator of gut microbiota is a more novel concept, although perhaps it shouldn’t be, as garlic is a source of inulin, a type of water-soluble prebiotic fiber. Inulin assists with digestion and absorption of your food and plays a significant role in your immune function.

Inulin is a fructan, which means it is made up of chains of fructose molecules. In your gut, inulin is converted into short-chain fatty acids (SCFAs) that are then converted to healthy ketones that feed your tissues.

Aged Garlic Extract May Benefit Your Brain

Previous research has also highlighted the benefits of a specific type of garlic — aged garlic extract (AGE) — for brain health. Known to have strong anti-inflammatory effects, AGE improved short-term recognition memory and relieved neuroinflammation in rats with an Alzheimer’s-like disease.5

The study used fresh garlic that was aged in order to create aged garlic extract, which produces beneficial organosulfur compounds including s-allyl cysteine (SAC), which is found in far greater quantities in aged garlic and black fermented garlic than it is in raw garlic.

AGE also contains thiosulfinates that have antioxidant effects, and more than 350 studies have demonstrated its safety and effectiveness in humans. AGE may protect the brain in a number of ways, including:6

  • Protect against neurodegenerative conditions
  • Prevent brain injury following ischemia
  • Protect neuronal cells against apoptosis
  • Preventing β-amyloid-induced oxidative death

“Moreover,” researchers explained in the journal Nutrients, “treatment with AGE or S-allyl cysteine has been shown to prevent the degeneration of the brain’s frontal lobe, improve learning and memory retention, and extend life span.”7

Aged garlic extract has also been found to improve gut microbiota, including increased microbial richness and diversity after three months of use.8 AGE and SAC have even been highlighted as potential preventative and therapeutic agents for Alzheimer’s disease.9 That being said, fresh garlic has also shown promise for memory function, including one study in which rats fed garlic had increased memory retention.10

Garlic Has Been Prized Since Ancient Times

The value of garlic has been recognized for centuries. There are references to garlic on Sumerian clay tablets dating back to 2600 B.C. In ancient Egypt, garlic was given to the working class to support heavy labor. And in the first Olympic games in Greece, the athletes ate garlic to increase stamina.11

In ancient Chinese medicine, garlic was used for digestion and to treat diarrhea and worm infestations, while in India, garlic was used for general healing as well as to treat fatigue, parasites, digestive issues, heart disease and arthritis.12

“It is fascinating to observe how cultures that never came into contact with one another came to the same conclusions about the role of garlic in health and disease. If folk wisdom is not ignored, it may teach us valuable lessons,” researchers wrote in Nutrition Journal, and many of these lessons are being backed by science today. They continued:13

“With the onset of Renaissance, increasing attention was paid in Europe to the medical use of garlic. A leading physician of the 16th century, Pietro Mattiali of Siena, prescribed garlic for digestive disorders, infestation with worms and renal disorders, as well as to help mother during difficult childbirth.

In England, garlic was used for toothache, constipation, dropsy and plague. In modern era scientists have been trying to validate many of these properties of garlic, specially in terms of the identity of the active components, their mechanisms of action and exploring the potential benefits as food supplements.”

Garlic Is Good for Your Heart

Garlic is known to prevent and treat a wide variety of cardiovascular and metabolic diseases, including atherosclerosis, thrombosis, high blood pressure and diabetes.14 Not only does it stimulate immune function, enhance detoxification and exert an antimicrobial effect, but it has strong antioxidant powers that support health.

In addition, taking garlic powder had a protective effect on the elastic properties of the aorta in elderly adults. The aorta is the largest of your body’s arteries with the job of transporting blood from your heart to the rest of your body. Not only is aortic stiffness often seen with aging but it’s associated with an increased risk of heart disease, heart attack, heart failure and stroke.15

However, among elderly adults who took garlic powder, the age-related increases in aortic stiffness were attenuated, with researchers concluding, “These data strongly support the hypothesis that garlic intake had a protective effect on the elastic properties of the aorta related to aging in humans.”16

In separate research, consuming 2 grams of fresh garlic increased plasma concentrations of nitric oxide (NO) in healthy adults,17 which is beneficial for your heart and more. Nitric oxide is a soluble gas continually produced from the amino acid L-arginine inside your cells.

While nitric oxide is a free radical, it’s also an important biological signaling molecule that supports normal endothelial function and protects your mitochondria — the little “power stations” in your cells that produce a majority of your body’s energy in the form of ATP.

It’s a potent vasodilator, helping relax and widen the diameter of your blood vessels, and healthy blood flow allows for efficient oxygenation of tissues and organs, and aids in the removal of waste and carbon dioxide. Further, NO improves brain neuroplasticity by improving oxygenation of the somatomotor cortex, a brain area that is often affected in the early stages of dementia.18

Garlic Fights Infections, Cancer

Garlic has immune stimulating properties and as such may be useful for fighting off a variety of infections. When 146 adults received either a placebo or garlic supplement for 12 weeks, those taking the garlic had significantly fewer colds and if they were infected they recovered faster.19

In another study involving AGE (aged garlic extract), those taking the garlic had reduced cold and flu severity, reduced symptoms and fewer days of suboptimal functioning or missed work or school. “Garlic contains numerous compounds that have the potential to influence immunity,” according to researchers in the Journal of Nutrition.20

“These results suggest that AGE supplementation may enhance immune cell function and may be partly responsible for the reduced severity of colds and flu reported. The results also suggest that the immune system functions well with AGE supplementation, perhaps with less accompanying inflammation.”21

Toward this end, the cancer-fighting effects of garlic are also well established. Garlic has been shown to kill cancer cells in laboratory studies, as well as shown promise when consumed via your diet.

Those who consume high amounts of raw garlic also appear to have a lower risk of stomach and colorectal cancers.22 Furthermore, among people with inoperable forms of colorectal, liver or pancreatic cancer, taking an extract of aged garlic for six months helped to improve immune function, which suggests it may be useful for helping your immune system during times of stress or illness.23

The Many Types of Healthy Garlic

You can’t go wrong when eating garlic, but if you’re not fond of the pungent flavor or are looking to boost the health effects even more, consider black garlic, which is produced by “fermenting” whole bulbs of fresh garlic in a humidity-controlled environment in temperatures of about 140 to 170 degrees F for 30 days.

Once out of the heat, the bulbs are then left to oxidize in a clean room for 45 days. This lengthy process causes the garlic cloves to turn black and develop a soft, chewy texture with flavors reminiscent of “balsamic vinegar” and “soy sauce,” with a sweet “prune-like” taste.24 Even garlic haters may love the taste of black garlic, and this superfood has been found to have more antioxidant activity compared to fresh.25

Writing in Molecules, researchers noted, “[S]ome people are reluctant to ingest raw garlic due to its unpleasant odor and taste. Therefore, many types of garlic preparations have been developed to reduce these attributes without losing biological functions. Aged black garlic (ABG) is a garlic preparation with a sweet and sour taste and no strong odor.”26

If you choose to eat fresh garlic, be aware that the fresh clove must be crushed or chopped in order to stimulate the release of an enzyme called alliinase, which in turn catalyzes the formation of allicin, which rapidly breaks down to form a number of different beneficial organosulfur compounds. So to “activate” garlic’s medicinal properties, compress a fresh clove with a spoon or chop it finely before to swallowing it.

If you’re worried about garlic breath, it’s a small price to pay for the many health benefits you’ll receive, but you can cut back on any resulting unpleasant odor by chewing raw apple, mint leaves or lettuce. All of these natural foods have been found to significantly reduce garlic breath,27 so you can eat garlic to your heart’s content without worrying about offending others.

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This Five-Minute Breathing Exercise Can Boost Brain and Heart Health

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The way you breathe has a significant impact on your health, and various breathing exercises have been shown to improve your health and well-being in a number of ways.

Most recently, researchers have found inspiratory muscle strength training — a technique that strengthens your respiratory musculature — can improve cardiovascular health, as well as cognitive and physical performance.

Inspiratory muscle strength training (IMST) involves inhaling through a hand-held device that restricts air flow. By making you work harder to breathe in, you strengthen the muscles used for inhalation. The inspiratory muscle trainer device was originally developed for people with respiratory conditions, and to help wean patients off mechanical ventilation.

As you might expect, your breathing muscles, including your diaphragm, will lose strength and atrophy from lack of use, just as other muscles in your body, and research1 shows that strengthening the breathing muscles improves weaning outcome in patients that have become too weak to breathe on their own after being on a ventilator.

How Inspiratory Muscle Strength Training Benefits Your Health

In the featured study, the preliminary results of which were presented at the annual Experimental Biology conference2 in Orlando, Florida, the researchers investigated how IMST might affect vascular, cognitive and physical health in middle-aged adults. 

A previous study3 had shown patients with obstructive sleep apnea who used the device to perform 30 inhalations per day for six weeks lowered their systolic blood pressure by an average of 12 millimeters of mercury (mm/Hg).

As reported by Medical News Today,4 “Exercising for the same amount of time usually only lowers blood pressure by half that amount, and the benefits seem to exceed those normally achieved with hypertension medication.”

Intrigued by these findings, the researchers, led by Daniel Craighead, postdoctoral researcher at the University of Colorado Boulder’s Integrative Physiology of Aging Laboratory, decided to investigate whether IMST might be useful for middle-aged adults who resist exercise.5,6,7

Indeed, those who used IMST not only lowered their blood pressure and improved their vascular health, they also improved their exercise tolerance, assessed through treadmill tests, and cognitive performance, assessed through cognitive tests. Craighead commented on the results:8,9

“IMST is something you can do quickly in your home or office, without having to change your clothes, and so far it looks like it is very beneficial to lower blood pressure and possibly boost cognitive and physical performance.

High blood pressure is a major risk factor for cardiovascular disease, which is the number one cause of death in America. Having another option in the toolbox to help prevent it would be a real victory …

I think IMST has slowly evolved from something used only by a very sick population to being something that people can adopt as a part of their everyday lifestyle. Maybe they won’t do 30 minutes of aerobic exercise, but perhaps they’ll do five minutes of this and get some benefits.”

Over Breathing — One of the Most Common Breathing Errors

When it comes to breathing, most people actually do it incorrectly, and the ramifications for your health can be significant. One of the most common errors is over breathing. By breathing more than necessary, you deplete your carbon dioxide (CO2) reserves. While it’s important to remove CO2 from your body, you need a balance of oxygen and CO2 for optimal function.

CO2 is not just a waste product but has actual biological roles, one of which is assisting in oxygen utilization. When your CO2 level is too low, changes in your blood pH impair your hemoglobin’s ability to release oxygen to your cells. This is known as the Bohr effect.10,11

CO2 also helps relax the smooth muscles surrounding your blood vessels and airways, which is why over breathing results in both airway and blood vessel constriction. You can test this by taking five or six big breaths in and out of your mouth.

Most people will begin to experience some light-headedness or dizziness. While you might reason that taking bigger breaths through your mouth allows you to take more oxygen into your body, which should make you feel better, the opposite actually happens.

This is because you’re expelling too much CO2 from your lungs, which causes your blood vessels to constrict — hence the light-headedness. The reality is that the heavier you breathe, the less oxygen is delivered throughout your body due to lack of CO2.

How Over Breathing Affects Your Health

Typical characteristics of over breathing include mouth breathing, upper chest breathing, sighing, noticeable breathing during rest and taking large breaths before talking. Normal breathing volume is between 4 and 7 liters of air per minute, which translates into 12 to 14 breaths per minute. Breathing more than this is often an indication of poor health.

For example, clinical trials12 involving asthmatics show they breathe between 10 to 15 liters of air per minute and people with chronic heart disease tend to breathe between 15 to 18 liters of air per minute. Mouth breathing in particular is also associated with a number of health problems, including:

Dehydration

Snoring13

Sleep apnea14,15,16,17

Asthma18 — In one study,19 young asthma patients had virtually no exercise-induced asthma after exercising while breathing through their noses. However, they did experience moderate bronchial constriction after exercising while mouth breathing. Research shows mouth breathing may increase asthma morbidity by increasing sensitization to inhaled allergens20

Abnormal facial development21 — Children who breathe through their mouths tend to develop longer faces with altered jaw structures22,23,24,25,26,27

Poor oral hygiene — Loss of moisture dries out your saliva and contributes to poor oral hygiene; dehydration causes your airways to constrict and makes nose breathing even more difficult, creating a vicious cycle

Reduced oxygen delivery to your heart, brain and other tissues due to constricted arterial blood flow28

Crooked teeth29

Poor posture30

Poor sports performance31,32 — This occurs primarily as a side effect of postural changes associated with mouth breathing that decrease muscle strength and inhibits chest expansion.33 Breathing through your nose also boosts air resistance by approximately 50% compared to breathing through your mouth.

As a result, you end up increasing your oxygen intake by 10% to 20% when nose breathing.34 The deeper and more rapid your breath (which is a hallmark of hyperventilation and mouth breathing), the more constricted your blood vessels will be and the less oxygen will be delivered to your tissues,35 and this lack of oxygen will also hamper sports performance

Attention-deficit hyperactivity disorder36

How to Breathe Properly

To minimize the problems associated with mouth breathing and over breathing, you need to breathe more lightly and through your nose. Ideally, your breath should be so light as to barely move the hairs inside your nose.

Breathing through your nose slows your breathing and makes it more regular, thereby improving oxygenation. Nasal breathing also activates your parasympathetic nervous system, which has a calming and blood pressure lowering effect.37,38

The following steps will help your breath become lighter. While you may feel a slight air shortage at first, this should be tolerable for most people. If it becomes uncomfortable, take a 15-second break and then continue.

  1. Place one hand on your upper chest and the other on your belly; feel your belly move slightly in and out with each breath, while your chest remains unmoving.
  2. Close your mouth and breathe in and out through your nose. Focus your attention on the cold air coming into your nose and the slightly warmer air leaving it on the out breath.
  3. Slowly decrease the volume of each breath, to the point it feels like you’re almost not breathing at all. The crucial thing here is to develop a slight air hunger. This simply means there’s a slight accumulation of carbon dioxide in your blood, which signals your brain to breathe.

After three or four minutes of air hunger, you’ll start experiencing the beneficial effects of CO2 accumulation, such as an increase in body temperature, a sign of improved blood circulation, and an increase in saliva, which is a sign of parasympathetic nervous system activation, which is important for stress reduction.

While mouth breathing tends to lead to over breathing, failure to exhale fully may also be part of the problem that’s causing you to over breathe. Oftentimes, it’s a combination of sucking in excessive air and exhaling incompletely. You’re your exhalation is incomplete, you end up with excess residual air in your lungs, and it is this that makes you feel short of breath.

The answer for this is not to breathe more but to breathe out more fully. You can train yourself to exhale more fully by making sure your exhale is slightly longer than your inhale, and by engaging your diaphragm to really squeeze the air out as you allow your midsection to collapse inward. The vertical breathing exercise below will also help strengthen your diaphragm, which will allow you to exhale more fully.

Vertical Breathing — Another Common Breathing Mistake

Another near-universal breathing abnormality is breathing vertically rather than horizontally. This is something clinical psychologist Belisa Vranich points out in her book “Breathe,” which details her breathing program. The condensed version of Vranich’s interview is included above for your convenience. For the full interview, see “Breathing Program to Improve Mental and Physical Health.”

Vertical breathing makes you feel a bit taller on the in-breath, as it raises your chest and shoulders. The problem is that this kind of breathing actually triggers your sympathetic nervous system. In other words, it triggers your stress response, which is the complete opposite of what you want.

Correct breathing will cause your midsection to widen while not raising your shoulders or puffing out the upper part of your chest. This is the horizontal breath. At first, you may find it difficult to take a proper breath, as your midsection and diaphragm may be tight. To relearn proper horizontal breathing, Vranich suggests the following exercise. In time, this exercise will teach your body to use the diaphragm to breathe.

  1. Begin by relaxing and unbracing your midsection.
  2. Take a deep breath in and actually feel the middle of your body get wider. Let your belly go.
  3. On the exhale, roll backward, tipping your hips underneath you while pressing your fingers gently into your belly, giving it a little squeeze.

As mentioned earlier, feeling short of breath is often caused by insufficient exhalation. Engaging your diaphragm and intercostals — the muscles that run between your ribs, allowing your chest wall to move — will allow you to take more complete in and out breaths.

The Link Between Athletic Endurance and CO2 Tolerance

While breathing through your mouth may be particularly tempting during physical exertion, try to avoid this tendency as it will actually diminish your fitness and endurance. Ideally, you would exercise only to the extent that you can continue breathing through your nose the vast majority of the time.

If you feel the need to open your mouth, then slow down and recover. This helps your body to gradually develop a tolerance for increased CO2. Dr. Konstantin Pavlovich Buteyko39 — the Russian physician after whom the Buteyko Breathing Method is named — discovered that the level of CO2 in your lungs correlates to your ability to hold your breath after normal exhalation.

This breath-holding capacity is known as your control pause or CP number. To identify your CP, which will give you an estimate of your CO2 tolerance, perform the following self-test.

1. Sit straight without crossing your legs and breathe comfortably and steadily.

2. Take a small, silent breath in and out through your nose. After exhaling, pinch your nose to keep air from entering.

3. Start your stopwatch and hold your breath until you feel the first definite desire to breathe.

4. When you feel the first urge to breathe, resume breathing and note the time. This is your CP. The urge to breathe may come in the form of involuntary movements of your breathing muscles, or your tummy may jerk or your throat may contract.

Your inhalation should be calm and controlled, through your nose. If you feel like you must take a big breath, then you held your breath too long.

The following criteria are used to evaluate your CP result:

CP 40 to 60 seconds — Indicates a normal, healthy breathing pattern and excellent physical endurance.

CP 20 to 40 seconds — Indicates mild breathing impairment, moderate tolerance to physical exercise and potential for health problems in the future (most folks fall into this category).

To increase your CP from 20 to 40, physical exercise is necessary. You might begin by simply walking with one nostril occluded. As your CP increases, begin incorporating jogging, cycling, swimming, weightlifting or anything else to build up an air shortage.

CP 10 to 20 seconds — Indicates significant breathing impairment and poor tolerance to physical exercise; nasal breath training and lifestyle modifications are recommended. If your CP is less than 20 seconds, never have your mouth open during exercise, as your breathing is too unstable. This is particularly important if you have asthma.

CP under 10 seconds — Serious breathing impairment, very poor exercise tolerance and chronic health problems.

Short CP times correlate with low tolerance to CO2 and chronically depleted CO2 levels. As a result, the shorter your CP, the more easily you’ll get breathless. The good news is that you will feel better and improve your exercise endurance with each five-second increase in your CP.

How to Increase Your CP and Boost Exercise Endurance

The following breath hold exercise will help increase your CP over time. While this exercise is perfectly safe for most, if you have any cardiac problems, high blood pressure, are pregnant, have Type 1 diabetes, panic attacks or any serious health concern, then do not hold your breath beyond the first urges to breathe.

Repeat this exercise several times in succession, waiting 30 to 60 seconds between rounds. Also, be sure to do it on a regular basis, ideally daily.

  • Sitting up straight, take a small breath in through your nose and a small breath out. If your nose is quite blocked, take a tiny breath in through the corner of your mouth.
  • Pinch your nose with your fingers and hold your breath. Keep your mouth closed.
  • Gently nod your head or sway your body until you feel that you cannot hold your breath any longer.
  • When you need to breathe in, let go of your nose and breathe gently through it, in and out, with your mouth closed. Calm your breathing as soon as possible.

For Optimal Health, Learn to Breathe Properly  

As mentioned, a normal breathing volume is around 12 to 14 breaths per minute, but research40 published in the medical journal Breathe suggests an optimal respiration rate is in the range of just six to 10 breaths per minute, and done in a way that activates your diaphragm.

Slowing your breathing to 10 breaths per minute or less has been shown to beneficially impact your respiratory, cardiovascular, cardiorespiratory and autonomic nervous systems.41 As noted in the Breathe study:42

“Controlled, slow breathing appears to be an effective means of maximizing HRV [heart rate variability] and preserving autonomic function, both of which have been associated with decreased mortality in pathological states and longevity in the general population.”

Aside from the breathing techniques already mentioned, there are many others that can be equally helpful. Following is a short list of a few additional breathing methods you can try, all of which are backed by scientific evidence43 showing their beneficial influence on human health.

Nadi Shodhana/Nadi Shuddhi (alternate nostril breathing) — With your right thumb, close the right nostril and inhale through your left nostril. Closing the left nostril, exhale through the right, following which, inhalation should be done through the right nostril. Closing the right nostril, breathe out through your left nostril. This is one round. The procedure is repeated for the desired number of rounds.

Surya Anuloma Viloma (right uninostril breathing) — Closing the left nostril, both inhalation and exhalation should be done through your right nostril, without altering the normal pace of breathing.

Chandra Anuloma Viloma (left uninostril breathing) — Similar to Surya Anuloma Viloma, breathing is done through your left nostril alone, by closing the right nostril.

Surya Bhedana (right nostril initiated breathing) — Closing the left nostril, inhalation should be done through your right nostril. At the end of inhalation, close the right nostril and exhale through the left nostril. This is one round. The procedure is repeated for the desired number of rounds.

Ujjayi (psychic breath) — Inhalation and exhalation are done through the nose at a normal pace, with partial contraction of the glottis, which produces a light snoring sound. You should be aware of the passage of breath through your throat during the practice.

Bhramari (female honeybee humming breath) — After a full inhalation, closing the ears using your index fingers, you should exhale making a soft humming sound similar to that of a honeybee.

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Amyloid-β is not Merely Molecular Waste

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Alzheimer’s disease begins with the accumulation of amyloid-β in the brain, but this doesn’t mean that amyloid-β is purely molecular waste. Yes, it is harmful given the presence of too much of it in the central nervous system, but that is true of most of our biochemistry. There is good evidence for amyloid-β to act as an antimicrobial system, for example, which is the basis for considering persistent infection as a potential contributing cause of Alzheimer’s disease, in which infectious agents drive the generation of ever increasing amounts of amyloid-β. Even setting aside that and other evidence, however, it is quite possible to argue that amyloid-β must have some important function, based on evolutionary theory and the fact that the molecule exists at all.


The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer’s disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide’s elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review whether evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide’s expression in senescence.

Aβ is an ancient neuropeptide expressed across vertebrates. Consistent with unusually high evolutionary selection constraint, the human Aβ sequence is shared by a majority of vertebrate species and has been conserved across at least 400 million years. Unlike humans, the overwhelming majority of vertebrate species do not cease reproduction in senescence and selection pressure is maintained into old age. Hence, low selective pressure in senescence does not explain the persistence of Aβ across the vertebrate genome.

The Grandmother hypothesis (GMH) is the prevailing model explaining the unusual extended postfertile period of humans. In the GMH, high risk associated with birthing in old age has lead to early cessation of reproduction and a shift to intergenerational care of descendants. The rechanneling of resources to grandchildren by postreproductive individuals increases reproductive success of descendants. In the GMH model, selection pressure does not end following menopause. Thus, evolutionary models and phylogenetic data are not consistent with the absence of reproductive selection pressure for Aβ among aged vertebrates, including humans.

Our analysis suggests an alternative evolutionary model for the persistence of Aβ in the vertebrate genome. Aβ has recently been identified as an antimicrobial effector molecule of innate immunity. High conservation across the Chordata phylum is consistent with strong positive selection pressure driving human Aβ’s remarkable evolutionary longevity. Ancient origins and widespread conservation suggest the human Aβ sequence is highly optimized for its immune role.

Link: https://doi.org/10.3389/fnagi.2019.00070

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Physical Activity, mTOR Signaling, and Alzheimer's Disease

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Alzheimer’s disease is a condition that sits atop a mound of many contributing causes, layered in chains of cause and effect. Given that chronic inflammation and age-related impairment of the cellular housekeeping mechanisms of autophagy both appear to be significant, somewhere in the mix, it is perhaps to be expected that many of the usual healthy lifestyle choices have some modest impact on the progression of the condition. Exercise and calorie restriction both act to upregulate autophagy and it is thought that this accounts for a sizable fraction of the resulting benefits to health and life span. Unfortunately, the sort of stress response upregulation appears to scale down in impact on life span as species life span increases, though the effects on short term health and metabolism appear quite similar. Mice can live up to 40% longer when on a calorie restricted diet, but that is certainly not true for humans; we gain a few years at most.

Autophagy recycles damaged structures and broken proteins inside the cell. Neurodegenerative conditions such as Alzheimer’s disease involve the presence of toxic molecules, such as those associated with amyloid-β and tau, but even if not directly involved in clearing away disease-associated damage, increased autophagy is generally protective of cell function. Given that this includes everything from neurons to the microglia responsible for clearing away intracellular debris and protein aggregates, we should expect increased autophagy to modestly improve just about every issue in the aging brain. Sadly, doing better than modest improvement is probably not within the scope of what might be achieved via increased rates of autophagy, even when researchers directly influence regulatory genes such as mTOR.

Physical Activity Alleviates Cognitive Dysfunction of Alzheimer’s Disease through Regulating the mTOR Signaling Pathway


Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including Alzheimer’s disease (AD). Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including amyloid-β (Aβ) production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration. As a result, autophagy has a crucial role in the regulation of longevity.

Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, AMPK, and GSK-3. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dysregulated mTOR signaling in AD. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, neurofibrillary tangles, and cognitive impairment in clinical presentation. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.

It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains. Interestingly, our recent study has also documented that the brain aging of d-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation. Therefore, physical activity is regarded as an effective approach against AD.

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Reviewing the Importance of the Blood-Brain Barrier in Brain Aging

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The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system, ensuring that only certain molecules can pass in either direction. Thus the biochemistry of the central nervous system is kept distinct from that of the rest of the body. This separation is necessary for correct function, as illustrated by the point that the blood-brain barrier begins to break down with advancing age. This produces damage and dysfunction in the brain, as unwanted cells and molecules leak through the faulty blood-brain barrier. As noted here, however, the relative scope and size of this contribution to neurodegeneration, in comparison to other contributing factors, is far from fully determined.


Changes in the immune system have long been recognized to occur with aging, and it is now appreciated that neuroinflammation likely contributes to age-associated neurological diseases. However, it is less well understood how specific changes in the immune system with aging may affect central nervous system (CNS) functions and contribute to neurological disease. We posit that brain barriers, especially the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces between CNS and peripheral tissues that are affected by age-associated changes in the immune system. The BBB/BCSFB may, in turn, affect homeostatic functions of the CNS, and/or exhibit more detrimental responses to pathological stimuli.

One of the most-studied (and yet, poorly understood) aspects of BBB dysfunction is disruption, which is typically defined by the apparent leakage of normally BBB impenetrant molecules. Recent imaging results argue that BBB disruption does occur in healthy aging, and is worse in individuals with mild cognitive impairment, which is considered a prodrome of Alzheimer’s disease (AD). One common approach to proxy BBB disruption in living humans is to measure the ratio of abundant, BBB-impermeant proteins such as albumin or immunoglobulin G (IgG) in cerebrospinal fluid (CSF) versus serum. However, these measures may be confounded by other known CNS deficits with aging, such as altered production and reabsorption of CSF, and inflammatory changes in the serum and CSF levels of these proteins. Further, there may be leakage of the BCSFB and altered protein synthesis at this site with age. Recent studies have implemented advanced imaging technologies that can visualize leakage of intravenously injected tracers via dynamic contrast MRI, and these have indicated that vascular BBB disruption does occur in the aging human brain, albeit at low levels.

In healthy aged mice, leakage of IgG into the parenchymal space of the cerebral cortex and hippocampus occurs when compared with young mice, suggesting that there is BBB disruption in this model. Increased IgG leakage in aged mice was associated with astrogliosis, endoplasmic reticulum (ER) stress, and increased endothelial cell levels of TNF-α; the latter measure significantly correlated with circulating levels of IL-6. In the same study, a significant reduction in occludin expression per brain endothelial cell was also observed in aged mice. Other studies have corroborated findings of BBB disruption in aging mice. Molecular mechanisms of BBB disruption in aging have been identified, and include reduced expression of sirtuin-1, a de-acetylase enzyme which has been implicated in the regulation of lifespan, senescence, and inflammatory responses to environmental stress.

BBB disruption in the context of aging or disease could result in disease exacerbation through leakage of potentially harmful proteins into the brain. However, it is not entirely clear that BBB disruption under any circumstance will always lead to brain damage. For example, certain therapeutic strategies for delivery of chemotherapeutics to the brain have relied on transiently disrupting the BBB, and are generally well-tolerated when brain cancers are the target. Recent work has also indicated that repeated transient BBB disruption in humans with AD using focused ultrasound did not cause any serious clinical or radiological adverse events. In contrast, healthy rodents with no prior brain abnormalities showed symptoms of reactive gliosis and neurodegeneration when transiently perfused with mannitol to cause widespread disruption of the BBB, and also had increased deposition of harmful serum proteins like fibrinogen in the CNS. The apparent paradox in efforts to disrupt the BBB as a therapeutic strategy versus BBB disruption having known adverse consequences on the CNS and associations with many CNS diseases highlights the complexities of BEC barrier functions that are likely nuanced and context-specific. Why BBB disruption in and of itself is apparently innocuous under some conditions, but clearly detrimental in others remains to be understood in greater molecular detail.

Link: https://doi.org/10.3390/ijms20071632

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Light Physical Activity Slows Brain Aging

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In recent years, with the enthusiastic adoption of accelerometers by the designers of epidemiological studies, it has become clear that even quite modest levels of physical activity correlate strongly with improved health and a slower pace of age-related degeneration. In most human data there is no way to establish which of these is cause and which of these is consequence, but animal studies are quite definitive on the point that exercise produces improvements in health, even if it doesn’t appear to extend life span. Physical activity, like all interventions, has a dose-response curve, and there is a sizable difference between being sedentary and being even modestly active. It is still a better idea to be more than just modestly active, of course; research suggests that the recommended levels of exercise, 150 minutes per week, may well be too low.


Considerable evidence suggests that engaging in regular physical activity (PA) may prevent cognitive decline and dementia. Active individuals have lower metabolic and vascular risk factors, and these risk factors may explain these individuals’ propensity for healthy brain aging. Even short-term exercise interventions have been shown to prevent hippocampal atrophy in older adults11 and may also improve brain connectivity. Furthermore, cross-sectional epidemiologic studies have established an association of physical inactivity with brain aging. However, further work is needed to pinpoint the optimal dosage of PA needed to promote healthy brain aging.

A growing body of literature has established light-intensity PA as an important factor for improving health outcomes, but in our review of the literature, light-intensity PA has not often been considered separately from total PA for its association with brain structure. Previous studies have identified positive associations of self-reported PA with brain volume, but accelerometry studies often have smaller sample sizes and have focused on examining the association of total PA with brain volume. However, PA variables are associated with one another, so in our analyses, we went a step further and modeled them together to determine what type of PA intensity (low or high) is driving the association of PA with brain volume.

The simplification of PA as a predictor variable has potentially masked more nuanced associations of components of PA with brain health. Compared with previous research, our study provides multiple PA levels and intensities and uses accelerometry-determined intensity thresholds (ie, light-intensity PA and moderate to vigorous PA) in the same statistical models to provide a more sensitive measure of PA doses and examine what type of PA is driving the associations we observe.

The study sample of 2354 participants had a mean age of 53 years, 1276 were women, and 1099 met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging. Among individuals not meeting the PA guidelines, each hour of light-intensity PA and achieving 7500 steps or more per day were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume.

Link: https://doi.org/10.1001/jamanetworkopen.2019.2745

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A New Approach to Targeting Tau Aggregation in Neurodegenerative Disease

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Researchers here report on discovering that an existing farnesyltransferase inhibitor drug reverses the accumulation of altered tau protein aggregates in a mouse model. The death and dysfunction of nerve cells in the neurodegenerative conditions known as tauopathies is driven by the formation of neurofibrillary tangles, made of tau protein. That in turn has deeper causes, such as the chronic inflammation produced by senescent cells and disruption of immune cell activity in the central nervous system, one of which is no doubt being adjusted in some way by the action of the drug in this case. As in all such quite indirect mechanisms, there is the question as to whether results in mice will translate to humans in any useful way. In the case of an existing drug, there is at least a shorter path to an answer.


Tau, a protein found primarily in neurons, is typically a somewhat innocuous, very soluble protein that stabilizes microtubules in the axon. However, when soluble, stable tau misfolds the resulting protein becomes insoluble and tangled, gumming up the works inside the neuron as a neurofibrillary tangle. In one of several neurodegenerative diseases caused by tau, frontotemporal dementia, the frontal and temporal lobes of the brain are impaired, resulting in problems with emotion, behavior and decision-making.

By taking skin cell samples from a few individuals who harbor tau mutations and converting them in vitro into stem cells, and then into neurons, researchers found that three genes were consistently disregulated in those with tau mutations, one of which was of particular interest: RASD2 – a gene expressed primarily in the brain that belongs in a family that catalyzes energy-producing molecules (GTPases) and which has been studied extensively. A GTPase called Rhes is encoded by the gene RASD2. Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where it is attached to the inner membrane by a small carbon chain – a farnesyl group – through a process called farnesylation.

This attachment has been the target of a couple decades and millions of dollars of cancer research under the assumption that if the Ras protein connection to the cell membrane could be interrupted, so would the signals that cause unregulated growth of tumor cells and other cancer behaviors. The drugs in this category, called farnesyltransferase inhibitors, have been tested in humans. But, they did not work in cancer.

In mice models with frontotemporal dementia, however, it seems they do. And the results are dramatic. Using the drug Lonafarnib, the researchers treated mice who at 10 weeks were erratic – running around in circles or completely apathetic – and by 20 weeks they were sniffing around their cage or nest building and doing other normal mouse behaviors. Scans revealed the arrest of brain tissue deterioration and inflammation. Most dramatic: The once-insoluble neurofibrillary tangles were greatly reduced, and in some areas including the hippocampus – the memory part of the brain – were nearly completely gone. To prove the drug was targeting the farnsylated Rhes protein, the scientists introduced into the brains of other mouse models an inhibitory RNA gene that specifically suppresses the production of Rhes. And the results completely replicated the effects of the drug.

Link: https://www.news.ucsb.edu/2019/019394/dissolving-gordian-knot

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A Demonstration of Amyloid-β Clearance via Affibodies in Mice

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While clearing out amyloid-β from the brain has so far proven to be a matter of too little, too late in late stage Alzheimer’s disease patients, there is still a strong basis of evidence for the merits of removing amyloid-β. It is reasonable to say that it causes meaningful pathology; if people did not accumulate amyloid-β deposits, then there would be no consequent disarray in the function of neurons and immune cells in the brain. This particular foundation of the development of dementia would be removed. Even if the mechanisms of the later stages of Alzheimer’s, the chronic inflammation and tau protein aggregation, for example, were blocked, then amyloid-β accumulation would still cause at least mild cognitive impairment on its own. Thus despite the continued failure of clinical trials, even those in which amyloid-β was in fact cleared to a fair degree from the brains of Alzheimer’s patients, we should still be encouraged by new approaches and other signs of progress in this area of the field.


Present therapies for Alzheimer’s disease (AD) have either no or minimal disease-modifying effect, and thus, there is an urgent need for new effective treatments. Numerous therapeutic strategies are under investigation to delay the onset or slow progression of the disease. Active and passive immunotherapeutic approaches have been suggested to improve clinical progression and cognitive impairment through different mechanisms: (i) inhibition of amyloid-β (Aβ) production; (ii) interference with the formation of toxic aggregation intermediates; and (iii) accelerated clearance of Aβ from the central nervous system into the periphery.

Several anti-Aβ antibodies have demonstrated effective clearance of Aβ together with cognitive improvements in transgenic animal models and consequently progressed to clinical trials. However, translation to safe and efficacious therapies for humans has been challenging as AD clinical trials have failed to show sufficient clinical benefits. Recently, the monoclonal antibody (mAb) Solanezumab, that binds monomeric Aβ, was extensively evaluated in a phase III prevention trial in patients with mild AD. The study was however terminated due to failure in showing cognitive improvements.

It has been proposed that challenges related to the failure in showing overall clinical improvement or clear disease-modifying results of these mAbs could be addressed to some of the inherent properties of antibodies. Thus, new approaches based on engineered antibody domains or alternative scaffold-proteins that generally lack immunoglobulin-related effector functions are now investigated and moving into clinical development, as they might provide safer and more effective treatments. Antibody derivatives and non-immunoglobulin affinity proteins are in general smaller than full-length antibodies. Their smaller size could potentially result in a different in vivo biodistribution profile as well as simplified administration routes, which could be important in the treatment of e.g., AD.

Affibody molecules represent a class of promising alternative scaffold proteins that have been investigated for various applications. We have previously reported on the generation of an affibody molecule (denoted ZAb3) that binds to monomeric Aβ. This Aβ-sequestering affibody molecule has demonstrated efficient inhibition of formation of Aβ aggregates in an in vivo Drosophila AD model, and abolished the neurotoxic effects as well as restored the life span of the flies. The affibody molecule was further engineered into a truncated genetic dimer, ZSYM73-ABD.

Encouraged by these positive results, we here investigate the efficacy of ZSYM73-ABD as a therapeutic candidate to prevent the development of AD-related pathology in transgenic AD mice. The animals received three weekly injections of 100 μg therapeutic protein or negative control protein during 13 weeks, starting at the expected onset of pathology development. Extensive behavioral assessment together with histological evaluation demonstrated a significantly lower amyloid burden in both cortex and hippocampus, as well as rescued cognitive functions of the ZSYM73-ABD treated mice relative to controls.

Link: https://doi.org/10.3389/fnagi.2019.00064

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